The Functions of BET Proteins in Gene Transcription of Biology and Diseases.

Ka Lung Cheung,Ming-Ming Zhou,Claudia Kim

doi:10.3389/fmolb.2021.728777

Ka Lung Cheung, Ming-Ming Zhou + Show 1 more

Open Access

https://doi.org/10.3389/fmolb.2021.728777

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Abstract

The BET (bromodomain and extra-terminal domain) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT, are widely acknowledged as major transcriptional regulators in biology. They are characterized by two tandem bromodomains (BDs) that bind to lysine-acetylated histones and transcription factors, recruit transcription factors and coactivators to target gene sites, and activate RNA polymerase II machinery for transcriptional elongation. Pharmacological inhibition of BET proteins with BD inhibitors has been shown as a promising therapeutic strategy for the treatment of many human diseases including cancer and inflammatory disorders. The recent advances in bromodomain protein biology have further uncovered the complex and versatile functions of BET proteins in the regulation of gene expression in chromatin. In this review article, we highlight our current understanding of BET proteins’ functions in mediating protein–protein interactions required for chromatin-templated gene transcription and splicing, chromatin remodeling, DNA replication, and DNA damage repair. We further discuss context-dependent activator vs. repressor functions of individual BET proteins, isoforms, and bromodomains that may be harnessed for future development of BET bromodomain inhibitors as emerging epigenetic therapies for cancer and inflammatory disorders.

Highlights

Bromodomain and extra-terminal domain (BET) family proteins, consisting of BRD2, BRD3, BRD4, and BRDT, are important transcription regulators, characterized by two N-terminal acetyl-lysine (Kac) binding bromodomains (BD1 and BD2) followed by an ET domain (Wu and Chiang, 2007; Zaware and Zhou, 2019) (Figure 1)
We summarize the recent advances in our understanding of the multi-faceted functions of BET proteins in gene transcription in chromatin
Targeting cells with BET-BD inhibitors has a strong impact on transcription but very little impact on enhancer–promoter interactions (Crump, 2021). These findings suggest that activation of transcription and maintenance of enhancer–promoter interactions are separable events and that BRD4 acts in activation of gene transcription through p-TEFb–mediated RNA Pol-II release from enhancer and promoter regions much more than in the maintenance of enhancer–promoter interactions

Summary

Introduction

Bromodomain and extra-terminal domain (BET) family proteins, consisting of BRD2, BRD3, BRD4, and BRDT, are important transcription regulators, characterized by two N-terminal acetyl-lysine (Kac) binding bromodomains (BD1 and BD2) followed by an ET domain (Wu and Chiang, 2007; Zaware and Zhou, 2019) (Figure 1). In addition to their role in gene transcriptional elongation, recent technological advancements have led to the discovery of other functions of BET proteins, including chromatin organization, super-enhancer assembly, and condensate formation. These results highlight the emerging concept that RNA/DNA-mediated mechanisms play a crucial role in the control of BRD4 chromatin binding and activity that contributes to gene transcriptional controls in diseases.

Results

Conclusion